John Michael Kaczmar, MD, medical oncologist, associate professor, College of Medicine, Medical University of South Carolina (MUSC), MUSC Health, discusses future implications forthe use of fianlimab (formerly REGN 3767) in combination with cemiplimab-rwlc (Libtayo) for the treatment of patients with advanced melanoma.

, data from a phase 1 study (NCT03005782) revealed that the combination of the LAG-3 inhibitor fianlimab and cemiplimab elicited high and consistent tumor responses. These responses were similar in toxicity profile to PD-L1 inhibitor monotherapies in patients with advanced melanoma who had not previously received PD-L1 inhibitors in the advanced setting. These outcomes indicate that dual PD-1/LAG-3 inhibition is effective and safe, even among patients who have undergone previous adjuvant immunotherapy and those with unfavorable prognostic characteristics.

Looking to the future, investigators are continuing to examine the utility and benefit of fianlimab when given with cemiplimab vs pembrolizumab (Keytruda), as measured by progression-free survival, in patients with advanced melanoma in a phase 3 trial (NCT05352672). Additionally, researchers are currently investigating fianlimab plus cemiplimab vs pembrolizumab monotherapy in the adjuvant setting in a phase 3 trial (NCT05608291), and they are in the process of validating it through more extensive studies, Kaczmar states. This research could introduce another effective treatment option for patients with recurrent/metastatic melanoma and may emerge as a superior choice for patients in the adjuvant setting, Kaczmar explains.

Furthermore, exploring combinations in the neoadjuvant setting is crucial, Kaczmar continues. For various cutaneous malignancies, specifically in more advanced cases, there is a growing trend toward employing neoadjuvant therapies, he says. This trend is not solely pertinent to melanoma, as skin alterations also encompass other cancerous conditions, he notes. Consequently, oncologists anticipate an increasing emphasis on neoadjuvant therapies, as thissetting is often the most opportune moment to administer immune therapy, Kaczmar states. Notably, the tolerability of this approach, which is associated with minimal additional toxicity, renders it as a potential treatment applicable across different stages of the disease continuum, Kaczmar concludes.

Videos

John Michael Kaczmar, MD, discusses future implications for the use of fianlimab in combination with cemiplimab for the treatment of patients with advanced melanoma.


Dr Kaczmar on the Future Utility of Cemiplimab With Fianlimab in Advanced Melanoma

Alexander I. Spira, MD, PhD, FACP, co-director, Virginia Cancer Specialists Research Institute, director, Thoracic and Phase I Program, clinical assistant professor, Johns Hopkins School of Medicine, discusses the evaluation of the LAG-3 inhibitor fianlimab plus cemiplimab-rwlc (Libtayo) in patients with advanced melanoma who were PD-L1 inhibitor–naïve, as seen in the findings from a phase 1 study (NCT03005782).

This was a substantially sized trial with various expansion cohorts across multiple tumor types, including melanoma, Spira begins. The focus of this expansion study was on patients with advanced melanoma who were naïve to immunotherapy (IO), he states. The study comprised 3cohorts, the first of which included patients who had not previously received IO treatment but were permitted to have prior non-IO treatment, Spira explains. The second cohort consisted of patients who had not undergone prior systemic therapy, most of whom had 

 V600E–mutant disease, he expands. The final cohort was made up of patients who would have otherwise received FDA-approved adjuvant systemic therapy, Spira notes, adding that thiscohort required patients to have a disease-free interval of at least 6 months.

This expansion trial had standard end points, with the primary end point being overall response rate (ORR), Spira expands. Notably, this trial also had typical secondary end points, such as progression-free survival, duration of response (DOR), disease control rate (DCR), safety, and pharmacokinetics, he explains. The preliminary results revealed an ORR of 61.2% among all patients enrolled in both the IO-naïve and systemic treatment–naïve arms. Within these cohorts, there were 12 complete responses and 48 partial responses, Spira says.

The DCR was 78%, the median DOR was not reached (95% CI, 23-not estimated [NE]), and the median PFS was 15.3 months (95% CI, 9.4-NE). In the subgroup of patients who had received prior neoadjuvant PD-1 therapy, the ORR rate was 61.5%, he explains. Overall, these data indicate that fianlimab plus cemiplimab is effective in different subgroups of patients with advanced melanoma, he concludes.

Alexander I. Spira, MD, PhD, FACP, discusses the evaluation of the LAG-3 inhibitor fianlimab plus cemiplimabin patients with advanced melanoma who were PD-L1 inhibitor–naïve, as seen in the findings from a phase 1 study.


Dr Spira on the Evaluation of Fianlimab Plus Cemiplimab in Advanced Melanoma

Meredith McKean, MD, MPH, director, Melanoma and Skin Cancer Research Program, Sarah Cannon Research Institute, discusses the rationale for investigating the LAG-3 inhibitor fianlimab (REGN3767) in combination with cemiplimab-rwlc (Libtayo) in patients with advanced melanoma, highlighting the combination's efficacy in both PD-1 inhibitor-exposed and –naïve populations, as well as the combinations itspotential clinical significance within the advanced melanoma space.

A phase 1, first-in-human study (NCT03005782) was conducted to evaluate the use of LAG-3 inhibition in combination with anti–PD-1 therapy to enhance treatment outcomes in patients with advanced melanoma. This approach was derived from the successes observed with other combination checkpoint inhibitors, such as ipilimumab (Yervoy) and anti-PD–1 agents, McKean explains. Although these combinations typically resulted in igh response rates, this often came at the cost of significant toxicity. In turn, this raised the question of whether response rates could be maintained with the addition of a LAG-3 inhibitor to a PD-1 inhibitor while minimizing treatment-related toxicity, McKean says.

The study included patients who received anti–PD-1 treatment in the neoadjuvant or adjuvant setting, as well as those who had not been previously exposed to a PD-1 inhibitor. Results were presented at the 2023 ASCO Annual Meeting.

In PD-1 treatment-naïve patients with metastatic or locally advanced disease, the LAG-3 inhibitor fianlimab plus the PD-1 inhibitor cemiplimab generated an overall response rate of 63.8% and a median progression-free survival (PFS) of 24.0 months, McKean reports. Notably, observed toxicity levels were not substantially higher than what would typically be expected with single-agent anti–PD-1 therapy, she states.

Additionally, response rates in patients who had previously been exposed to anti–PD-1therapy and subsequently experienced disease recurrence ranged from 50% to 60%, a result that exceeded expectations, McKean details. Many of these patients had completed their prior anti–PD-1 treatment or were not currently receiving it, potentially contributing to the favorable outcomes, McKean notes.

Further investigation is needed to confirm these findings in randomized studies, McKean continues. If validated, the combination of fianlimab plus cemiplimab may provide patients with a highly effective, yet less toxic alternative to ipilimumab (Yervoy) and nivolumab (Opdivo) in the front line, McKean states. Moreover, this approach holds promise for patients who developed refractory disease and for whom previous LAG-3 inhibitors have had limited efficacy, McKean adds. Additionally, combining LAG-3 and anti–PD-1 therapies in the adjuvant setting may improve outcomes for patients who previously had few treatment options, McKean says. The study's findings mark a significant step forward in advancing treatment options in melanoma while prioritizing patient safety and efficacy, she concludes.

Meredith McKean, MD, MPH, discusses the rationale for investigating the LAG-3 inhibitor fianlimab in combination with cemiplimab-rwlc in patients with advanced melanoma, highlighting the combination's efficacy in both PD-1 inhibitor-exposed and –naïve populations, as well as the combinations its potential clinical significance within the advanced melanoma space.

Dr McKean on the Rationale For Evaluating LAG-3 Inhibitors in Advanced Melanoma

The combination of fianlimab and cemiplimab-rwlc (Libtayo) represents a wave of novel anti–LAG-3/PD-1 treatments being explored in patients with melanoma at high risk for relapse, according to the rationale and design of an ongoing phase 3 trial (NCT05608291) that were presented at the 2023 ASCO Annual Meeting.

“The longer relapse-free survival [RFS] and lower toxicity has made PD-1 inhibitors the standard of care as adjuvant therapy in patients with high-risk melanoma,” Timothy J. Panella, MD, of the University of Tennessee Medical Center at Knoxville, said during a presentation of the trial in progress. “Despite these recent advances, a significant portion of patients will relapse. Hence, for patients with resectable high-risk melanoma, there is a high need for a treatment that is more efficacious than anti–PD-1 monotherapy with good tolerability.”

The immune checkpoint receptor LAG-3 is a potentially relevant therapeutic target in melanoma because it suppresses cytokine secretion and T-cell activation. Previously, in the phase 2/3 RELATIVITY-047 trial (NCT03470922), the fixed-dose combination of the LAG-3 inhibitor relatlimab-rmbw plus the PD-1 inhibitor nivolumab (Opdualag) produced a median progression-free survival (PFS) of 10.1 months compared with 4.6 months with nivolumab alone in patients with treatment-naïve metastatic or unresectable melanoma,

FDA approval of the combination in this population

Subsequently, a phase 1 first-in-human study (NCT03005782) demonstrated that in patients naïve to PD-1/PD-L1 inhibitors, the LAG-3 inhibitor fianlimab plus the PD-1 inhibitor cemiplimab generated an overall response rate of 63.8% and a median PFS of 24.0 months. The median duration of response was not reached in this population.

Supported by these findings, investigators designed a randomized, double-blind, 3-arm, phase 3 trial to evaluate the efficacy of the fianlimab/cemiplimab combination vs pembrolizumab (Keytruda) monotherapy in patients with completely resected high-risk melanoma.

This trial plans to enroll approximately 1530 patients at least 12 years of age with histologically confirmed, surgically resected stage IIC, III, or IV melanoma. Patients with stage IIIA melanoma need to have 1 or more micrometastasis in the lymph nodes with a diameter of over 1 mm. Up to 10% of the total trial population can consist of patients with acral or mucosal melanoma. Patients must have undergone complete surgical resection of their melanoma within 12 weeks prior to enrollment and need to be disease free within 4 weeks prior to enrollment. Patients are not permitted to have received prior systemic or radiation therapy for melanoma in the 5 years prior to enrollment, with the exception of patients with stage IV M1d disease, who may have received radiotherapy to the central nervous system after radical resection. In addition, patients need to have an ECOG performance status of 0 or 1, as well as a Karnofsky performance status or Lansky performance status over 70 in patients older than 16 years and younger than 16 years, respectively. At minimum, all patients must provide 25 slides or 125 mm3 of a resected tumor tissue sample.

Patients will be excluded if they have: uveal melanoma or evidence of residual disease following surgery per imaging, cytology, or pathology; evidence of clinically significant autoimmune disease that is ongoing or has occurred within 2 years prior to enrollment and required systemic immunosuppressive treatment; another malignancy that is currently progressing or required active treatment within 5 years prior to randomization; received prior anticancer therapy, including chemotherapy, immunotherapy, biological therapy, or major surgery within 5 years prior to randomization; received immunosuppressive corticosteroids amounting to over 10 mg of prednisone daily or an equivalent treatment, within 14 days prior to receiving the first dose of study treatment; and current evidence or history of significant local or systemic infection, defined as Common Terminology Criteria for Adverse Events grade 2 or higher, that required systemic antibiotic treatment within 2 weeks of receiving the first dose of study treatment. Adolescent patients, defined as those at least 12 years to under 18 years of age, who weigh less than 40 kg will also be excluded.

Patients will be stratified by disease stage (stage IIIA vs IIC-IIIB-IIIC vs IIID-IV[M1a/b] vs IV[M1c/d]) and geographical region (North America vs Europe vs Rest of World).

Patients will be randomly assigned 1:1:1 to receive fianlimab at dose 1 plus cemiplimab at 350 mg every 3 weeks intravenously (IV; arm A), fianlimab at dose 2 plus cemiplimab at 350 mg every 3 weeks IV (arm B), or pembrolizumab at 200 mg plus saline or dextrose placebo every 3 weeks IV (arm C). Patients will remain on the study treatment for 1 year.

The full analysis population, which will be used for efficacy analyses, will include all randomly assigned patients. The safety analysis population will include all randomly assigned patients who received any study drug.

The primary hypothesis of this trial is to demonstrate the superiority of fianlimab at either tested dose level plus cemiplimab over pembrolizumab as adjuvant treatment for patients with high-risk melanoma. The primary end point of this trial is RFS, with secondary end points including overall survival, melanoma-specific survival, distant metastasis-free survival, quality of life, safety/tolerability, the pharmacokinetics of fianlimab plus cemiplimab, and the immunogenicity of fianlimab and cemiplimab.

Panella TJ, Thomas SS, McKean M, et al. A phase 3 trial comparing fianlimab (anti–LAG-3) plus cemiplimab (anti–PD-1) to pembrolizumab in patients with completely resected high-risk melanoma. 

. 2023;41(suppl 16):TPS9598. doi:10.1200/JCO.2023.41.16_suppl.TPS9598

Tawbi HA, Schadendorf D, Lipson EJ, et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. 

. 2022;386(1):24-34. doi:10.1056/NEJMoa2109970

Hamid O, Lewis K, Weise A, et al. Phase 1 study of fianlimab, a human lymphocyte activation gene-3 (LAG-3) monoclonal antibody, in combination with cemiplimab in advanced melanoma. 

. 2022;33(suppl 7):S7905. doi:10.1016/j.annonc.2022.07.916

Articles

The combination of fianlimab and cemiplimab represents a wave of novel anti–LAG-3/PD-1 treatments being explored in patients with melanoma at high risk for relapse.

Anti–LAG-3/PD-1 Combination Under Investigation as Adjuvant Therapy in High-Risk Melanoma

Omid Hamid, MD, director, Melanoma Program, Cedars-Sinai Medical Center, chief, Translational Research and Immunotherapy, director, Melanoma Therapeutics, Phase I Immuno-Oncology Program, The Angeles Clinic and Research Institute, discusses the investigation of the LAG-3 inhibitor fianlimab (REGN3767) in combination with cemiplimab-rwlc (Libtayo) in patients with advanced melanoma who were naïve to anti–PD-1 agents in the advanced setting.

Data from a phase 1 trial (NCT03005782) presented at the 2023 ASCO Annual Meeting showed that across 3 cohorts of patients, including 1 that included those who received anti–PD-1 treatment in the neoadjuvant or adjuvant setting, the combination elicited an overall response rate of 61% (95% CI, 51%-71%). Notably, responses were observed across key subgroups, including patients with poor prognosis, such as those with high lactate dehydrogenase or liver/visceral metastases, Hamid says.

The median duration of response was not reached among all patients, and the estimated median progression-free survival was 15 months (95% CI, 9–not estimable).

Safety data showed the regimen was well tolerated, even in patients who received anti–PD-1 therapy in the adjuvant setting, and no new safety signals were observed, Hamid explains. Although the toxicities were similar to what would be expected from treatment with single-agent anti–PD-1 therapy, there was an increased incidence of adrenal insufficiency; however, these adverse effects were generally grade 1 or 2, and these events were resolved with steroids, Hamid notes.

Further investigation of fianlimab plus cemiplimab is currently ongoing for patients with melanoma, including those in the advanced setting in a phase 3 trial (NCT05352672), and in the adjuvant setting in another phase 3 study (NCT05608291). The combination is also being explored in triplets and in other settings, Hamid concludes.

Omid Hamid, MD, discusses the investigation of the LAG-3 inhibitor fianlimab in combination with cemiplimab in patients with advanced melanoma who were naïve to anti–PD-1 agents in the advanced setting.


Dr Hamid on the Investigation of Fianlimab With Cemiplimab in Advanced Melanoma

The LAG-3 inhibitor fianlimab plus cemiplimab (Libtayo) produced high and consistent tumor responses and a comparable toxicity profile to that of anti–PD-L1 monotherapies in patients with advanced melanoma who were PD-L1 inhibitor–naïve in the advanced setting, according to data from a phase 1 study (NCT03005782) presented at the 

The phase 1 study (NCT03005782) enrolled 98 patients, 13.3% of whom had received PD-1/PD-L1 inhibitors as adjuvant or neoadjuvant therapy. The objective response rate (ORR) for fianlimab/cemiplimab was 61.2% in all patients, 60.9% in patients with any adjuvant treatment, and 61.5% in those who had received adjuvant PD-1 therapy.

“In the combination of fianlimab and cemiplimab, we showed a consistent and reproducible high clinical activity in 3 independent cohorts of patients who were naive to anti–PD-1 in the advanced melanoma setting,” Omid Hamid, MD, chief of translational research and immunotherapy and director of melanoma therapeutics at The Angeles Clinic and Research Institute in Los Angeles, California, stated in his presentation. “Similar clinical activity was observed in patients treated with prior adjuvant therapies including anti–PD-1.”

Patients with unresectable or metastatic melanoma who had not received prior anti–PD-1/PD-L1 therapy for advanced disease were enrolled in 3 expansion cohorts of the study. Two of these cohorts had previously been reported on at an earlier data cut-off of July 1, 2022; in those results, the combination of the LAG-3 inhibitor fianlimab with the PD-1 inhibitor cemiplimab had an ORR of 62.5% in patients in an initial first or second-line cohort and a confirmatory first-line cohort which had both received no prior anti–PD-1/PD-L1 therapy.

Hamid presented updated results from these cohorts with a total of 40 patients in each cohort, plus 18 in an additional cohort of first-line patients with metastatic disease who had received prior adjuvant/neoadjuvant therapy. They received 1600 mg fianlimab plus 350 mg cemiplimab every 3 weeks for 12 months, with an additional 12 months if clinically indicated.1 Tumors were measured every 6 weeks for 24 weeks, then every 9 weeks thereafter.

The median age of patients was 68.0 years. Two percent of patients had received prior treatment for metastatic disease, 23.5% had received adjuvant or neoadjuvant systemic treatment with a disease-free interval of at least 6 months. The 13 patients who received adjuvant/neoadjuvant PD-1/PD-L1 therapy had been treated with nivolumab (Opdivo) or pembrolizumab (Keytruda). Thirty patients across the 3 cohorts had a 

At the data cut-off of November 1, 2022, the median follow-up was 12.6 months and the median duration of treatment was 32.9 weeks. Three patients (8%) in the initial cohort, 14 (35%) in the confirmatory cohort, and 5 (28%) in the prior adjuvant cohort were ongoing treatment; others had completed or discontinued therapy.

The RECIST 1.1-based investigator-assessed ORR of 61.2% included 12 complete responses (CR) and 48 partial responses (PR). The disease control rate was 78%. The median duration of response (DOR) was not reached (95% CI: 23-not estimated [NE]). The Kaplan-Meier estimated median progression-free survival (PFS) was 15.3 months (95% CI, 9.4-NE).

“Tumor responses in these cohorts together compared favorably with historical controls in relation to follow-up, overall response, disease control rate, and estimated median [PFS],” Hamid said.

When looking at the patients who had prior adjuvant therapy of any type, including 5 in the initial cohort, 14 out of 23 responded to the fianlimab/cemiplimab combination, with a median DOR that was not reached and a median PFS of 13.3 months. Adjuvant/neoadjuvant therapies included PD-1 agents, interferon, and BRAK/MEK-targeted treatments. For those who had received prior adjuvant nivolumab or pembrolizumab, 8 out of 13 responded to the combination, including 1 complete response. They had a median DOR that was not reached and a median PFS of 11.8 months.

A subgroup analysis was conducted for patients with poor prognosis melanoma including 21 with liver metastases, 32 with high baseline lactate dehydrogenase (LDH), and 17 M1c stage plus LDH greater than the upper limit of normal. These subgroups had an ORR of 43%, 53%, and 35%, respectively, and this analysis was also presented in detail by Inderjit Mehmi, MD, in a poster at the conference.

Fifty-five patients had LAG-3 expression of at least 1% and 26 had PD-L1 expression of at least 1%. According to Hamid, “In this cohort, efficacy was observed regardless of LAG-3 or PD-L1 tumor expression.”

In terms of safety, 43.9% had grade 3 or higher treatment-emergent adverse events (TEAEs) and 32.7% had serious TEAEs. Immune-related adverse events (irAEs) occurred in 65.3%, with 12% being grade 3 or higher. Patients required treatment discontinuation in 16.3% due to TEAEs. Rates of irAEs were similar to PD-1 monotherapy in general.

“Overall, the safety overview of this combination was generally consistent with the safety profile that we are familiar with of single-agent cemiplimab and other anti–PD-1 agents,” Hamid said. “Only adrenal insufficiency, at a rate of 11%, appeared to be higher in this cohort, most grade 1 or 2, and all cases successfully managed with steroid replacement.” One case of adrenal insufficiency was associated with treatment discontinuation.

A phase 3 trial (NCT05352672) of fianlimab plus cemiplimab in treatment-naive advanced melanoma is currently underway with a targeted enrollment approximately of 1590 patients. It includes 4 arms including 1 using the dose level of the phase 1 trial, 1 with a lower dose of fianlimab, and 2 comparator arms of pembrolizumab plus placebo and cemiplimab plus placebo. Another phase 3 trial (NCT05608291) is taking place in the adjuvant setting in comparison to pembrolizumab plus placebo.

These data support the efficacy and safety of the anti–PD-1/LAG-3 combination even in patients who have received prior adjuvant immunotherapy, as well as those with poor prognostic features.

Hamid O, Lewis KD, Weise AM, et al. Significant durable response with fianlimab (anti–LAG-3) and cemiplimab (anti–PD-1) in advanced melanoma: Post adjuvant PD-1 analysis. 

. 2023;41(suppl_16):9501. doi:10.1200/JCO.2023.41.16_suppl.9501

Hamid O, Weise AM, Kim TM, et al. Phase I study of fianlimab, a human lymphocyte activation gene-3 (LAG-3) monoclonal antibody, in combination with cemiplimab in advanced melanoma (mel). 

2022;33(suppl_7):S356-S409. doi:10.1016/annonc/annonc1059

The LAG-3 inhibitor fianlimab plus cemiplimab produced high and consistent tumor responses and a comparable toxicity profile to that of anti–PD-L1 monotherapies in patients with advanced melanoma who were PD-L1 inhibitor–naïve in the advanced setting, according to data from a phase 1 study.

Novel Approaches Under Evaluation in Melanoma | Supplements and Featured Publications

Dr Kaczmar on the Future Utility of Cemiplimab With Fianlimab in Advanced Melanoma

Dr Spira on the Evaluation of Fianlimab Plus Cemiplimab in Advanced Melanoma

Dr McKean on the Rationale For Evaluating LAG-3 Inhibitors in Advanced Melanoma

Anti–LAG-3/PD-1 Combination Under Investigation as Adjuvant Therapy in High-Risk Melanoma

Dr Hamid on the Investigation of Fianlimab With Cemiplimab in Advanced Melanoma

Fianlimab/Cemiplimab Demonstrates Early Clinical Activity and Safety in Advanced Melanoma